There is strong evidence that acute kidney injury (AKI) significantly increases the risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD). If AKI occurs in patients with CKD, the prognosis is significantly worse. Both clinical and basic science studies report that preexisting CKD impairs recovery from AKI and AKI accelerates the progression of preexisting CKD. However, the mechanisms contributing to such AKI-CKD interactions remain poorly understood. In this regard, two recent clinical studies indicate that administration of renin-angiotensin system (RAS) inhibitors during recovery from AKI significantly reduces mortality and CKD progression. Thus, administration of anti-hypertensive therapy (AHT) during a critical window following AKI may improve recovery and reduce the risk of CKD progression. As such, this proposal tests the hypothesis that the development or worsening of hypertension following AKI in preexisting CKD states impairs tubule recovery and is the major cause of the subsequent progression to ESRD. A novel rat model of the AKI?CKD nexus that we have shown recapitulates the impaired recovery from AKI and subsequent rapid progression to ESRD in the clinical setting will be used in the proposed studies. The first aim will investigate the role of hypertension and increased renal blood pressure transmission to promote renal inflammation, pericyte dysfunction, microvascular rarefaction, and hypoxia during recovery from AKI in preexisting CKD states. We propose that hypoxia hinders the ability of injured tubular epithelial cells to redifferentiate and regain function. To test this, we will administer RAS dependent and independent AHT?s beginning 1 week following AKI to assess the extent to which they alter renal pericyte density, capillary density, hypoxia, and tubular differentiation status. Consistent with our preliminary data, we anticipate that reducing BP, per se, will mitigate microvascular rarefaction and hypoxia, promote tubular epithelial cell redifferentiation, and reduce the development of fibrosis during recovery from AKI. We will also use multiplex ELISA cytokine arrays to determine the ability of different AHT?s to mitigate renal pro-inflammatory cytokine production during recovery from AKI in rats with preexisting CKD. Studies in Aim 2 will utilize gold standard blood pressure measurements in conscious, chronically instrumented rats to investigate the extent to which even modest increases in blood pressure following AKI in rats with preexisting CKD contribute to the progression of CKD. Novel analytical methodologies will also be used to assess renal blood flow autoregulation in conscious rats over several weeks after AKI. These studies employ an innovative animal model and physiological, biochemical, and immunological approaches to examine the poorly understood mechanisms contributing to impaired recovery and the rapid progression to ESRD after AKI in settings of preexisting CKD. In addition to providing novel insights into the clinical AKI-CKD nexus, these experiments may lead to new treatment strategies or therapeutic targets that could be used to improve recovery from AKI and reduce the subsequent risk of CKD progression in this at-risk population.